Aging is not only an important biological phenomenon but a core basis in many deleterious aging-related diseases. Having appreciated that IKKb/NF-kB-dependent inflammation mediates hypothalamic mechanism of aging, the long-term objective of this research is to study the involved neural types and molecular cascades, in order to develop strategies for treating aging-related diseases. In preliminary studies, hypothalamic astroglia have been targeted, using mouse models of astroglia-specific IKKb/NF-kB activation or inhibition. Preliminary data have demonstrated IKKb/NF-kB activation or inhibition in hypothalamic astroglia was sufficient to lead to aging acceleration or retardation, respectively. Hence, supported by these data, the hypothesis of this project is that astroglial IKKb/NF-kB is activated during early aging to induce neuronal inflammation and thus mediates the hypothalamic mechanism of aging. This hypothesis predicts that astroglial IKKb/NF-kB inhibition can reduce aging-related hypothalamic neuronal inflammation and therefore provide anti-aging effects. This hypothesis will be examined in 3 Aims: (1) Study the role of astroglial IKKb/NF-kB in aging-related hypothalamic inflammation; (2) Study the role of brain or hypothalamic astroglial IKKb/NF-kB in aging physiology and lifespan; (3) Study the neuronal mechanism in astroglial IKKb/NF-kB -mediated aging development. Experiments in these Aims will be carried out by using mouse models of site- and cell type-specific IKKb/NF-kB activation or inhibition. A list of molecular methods will be used to analyze astroglial and neuronal inflammatory changes as well as the inhibitory impacts on anti-aging molecular markers such as SIRTs and FOXOs. Also, a battery of physiological and histological approaches will be used to analyze aging of mouse models. Overall, successful completion of this project can yield new insights into the hypothalamic mechanism of aging, and enlighten a potential of targeting the hypothalamus for managing healthy aging and counteracting deadly aging-related diseases.